Benign prostatic hyperplasia (BPH) is a benign prostate condition characterized histologically by hyperplastic nodules in the periurethral region and transition zone of the prostate, and clinically by an enlarged prostate and lower urinary tract symptoms (LUTS). BPH-related outcomes and LUTS, which we refer to as BPH/LUTS, are extremely common among older men, leading to considerable bother and decreased quality of life, as well as severe complications, such as acute urinary retention and, in the most severe cases, death. Costs associated with management and treatment of this common condition are tremendous. In the year 2000 alone, BPH/LUTS management and treatment cost over $1.1 billion in the U.S. Therefore, given the considerable costs and negative impact of BPH/LUTS on older men's quality of life, identification of modifiable risk factors for BPH/LUTS development and their timing of action is crucial to inform effective primary prevention strategies. Energy balance, measured as body size and physical activity (PA), shows promise as a modifiable cause of BPH/LUTS. Several studies of later-life body size and PA have observed positive associations for body size, and inverse associations for PA with BPH/ LUTS, suggesting that energy balance may contribute to BPH/LUTS. However, most of these studies were limited to prevalent BPH/LUTS, making their findings susceptible to reverse causation and recall bias. Very few studies have investigated body size and/or PA in relation to incident BPH/LUTS and, of these few studies, most have observed null associations, drawing into question prevalent findings. Other unanswered questions include the possible timing of influence of body size and PA on BPH/LUTS development and the joint influence of these two factors. Therefore, to address these important research gaps, we propose to investigate body size and PA at baseline, as well as earlier in life, across adulthood, and jointly in relation to incident BPH/LUTS in the large Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial. The proposed analyses are innovative because they will be one of only a few studies to investigate body size and PA in relation to incident BPH/LUTS;one of only a few to examine body size and PA earlier in life and across adulthood in relation to BPH/LUTS, and the first, to our knowledge, to investigate the joint influence of body size and PA on BPH/LUTS risk. The proposed analyses are significant because they hold the promise to inform novel, effective and tailored primary prevention strategies for BPH/LUTS development, including both the nature of possible interventions, e.g., whether PA maintenance or body size reduction is more important to stress in a "fat and fit" man;as well as the necessary timing of interventions, i.e., whether body size reduction and/or increase in PA need to be stressed earlier in life, or whether changes in body size and PA later in life may still reduce BPH/LUTS risk. Novel prevention strategies for BPH/LUTS are critical to reduce the incidence of this extremely common and bothersome condition, and ease its substantial economic and health burden. PUBLIC HEALTH RELEVANCE: The proposed secondary data analyses are relevant to public health because they will determine whether large body size (e.g., overweight and obesity) and lesser physical activity contribute to the development of benign prostatic hyperplasia (BPH)/lower urinary tract symptoms (LUTS) in middle- and older-aged men. If our findings are promising, these could guide the development of novel, effective, and tailored primary prevention strategies for BPH/LUTS based on reduction or maintenance of body size and increase or maintenance of physical activity in men. Novel primary prevention strategies for BPH/LUTS are crucial to reduce the incidence of this extremely common and bothersome condition, and ease its tremendous financial and health toll.